Most of the commercially valuable proteins have been currently produced by culture of a host cell capable of expressing the gene of such protein.
The production of a protein by a culture technique or genetic recombination is based on the mechanism allowing production of a desired protein along with the exponential functional proliferation of the host cell. For the productivity of the protein to increase, it is needed to prepare or control the culture environment of the host cell, so that the performance of the host cell (function of cell) can be most effectively utilized. For this end, a variety of methods suitable for culture production have been investigated in terms of the culture process for producing the desired protein in a short time with high production efficiency and high yield.
There is a close relationship between the specific growth rate of the host cell and the amount of the protein produced by said host cell, and the maximum production of the protein requires control of the specific growth rate of the host cell to maintain same at an optimal value. To achieve this, the relationship between the amount of the product produced by the host cell (microorganism) and specific growth rate thereof has been heretofore studied from various aspects, which led to the suggestion of numerous models.
According to these models, it sometimes happens that the specific growth rate of the cell should be varied at least once during culture to increase the amount of production [Hakko KogakuKaishi, vol. 70, No. 5, pp. 395-404 (1992)].
However, the studies by the present inventors have firstly revealed that the variation of the specific growth rate aiming at optimization of the culture does not lead to an increase in the amount of production of the objective product to a desired degree (present specification, Example 1).
Hence, a culture method is demanded to increase the productivity of the desired product produced by the host cell, which is capable of efficiently producing the product without affecting the performance of the host cell due to the changes in the specific growth rate of the host cell.
It is therefore an object of the present invention to provide a method for producing a protein, comprising controlling, in a fed-batch culture system, the specific growth rate .mu. of the host cell by changing the feeding rate of a substrate into a medium, thereby to produce the desired protein in large amounts in a short time.
Another aspect of the present invention deals with the provision of a method for culturing the host cell capable of producing the desired protein in a highly efficient manner.